Discovery of Novel Small Molecule HDAC1, 2, 3 Inhibitors -- Combined Receptor-Based and Ligand-Based Virtual Screening Strategy

2021 ◽  
Vol 19 ◽  
Author(s):  
Yi Wu ◽  
Bo Zhang ◽  
Xiaowu Dong ◽  
Shenglin Ma ◽  
Shengquan Hu
Keyword(s):  
Virtual Screening ◽  
Small Molecule ◽  
Inhibitory Activity ◽  
Histone Deacetylases ◽  
Therapeutic Potential ◽  
P53 Gene ◽  
Screening Strategy ◽  
Binding Modes ◽  
Histone Deacetylase 1

Aims: To investigate and validate the potential drug target to HDAC1. Background: Human histone deacetylase 1 (HDAC1) can catalyze the deacetylation of histones belongs to the family of human histone deacetylases (HDACs). As an amide hydrolase HDAC1 plays a key role in the development of many serious cancers such as prostate cancer, gastric cancer, lung cancer, esophageal cancer, colon cancer, and breast cancer. Therefore, HDAC1 inhibitors, promoting the transcription of a series of key genes such as the p53 gene and inhibiting the development of cancer through various downstream mechanisms, have great potential for the treatment of cancer. Objective: To discover new skeleton HDAC1 inhibitors efficiently and conveniently with therapeutic potential for cancer. Method: Based on the crystal structure of HDAC1, through the combination of receptor-based and ligand-based virtual screening from the commercial compound library, the top-ranked compounds are selected for purchase through binding modes analysis, and their activities were verified through in vitro HDAC1 inhibitory biological experiments Results: Based on LeDock, 5ICN shown good distinguishing ability and was used as the receptor. According to the results of the LeDock docking scoring from receptor-based virtual screening, 69 compounds with binding energy less than -7.5 kcal/mol were obtained and used for ligand-based virtual screening. A total of 21 novel compounds with high potential HDAC1 inhibitory activity were collected by combining the similarity searching (NN) and the multinomial Naive Bayes machine learning model (NB) methods. Through binding modes analysis, 10 compounds with different structures with potential HDAC1 inhibitory activity were selected and screened HDAC1 inhibitory in vitro. May267 showed moderate HDAC1 inhibitory activity, and the inhibition rate was 48% at a concentration of 20 μM. Conclusion: This study discovers novel small molecule HDAC1 inhibitors by combined receptor-based and ligand-based virtual screening strategy, which provides an efficient method for the discovery of other small molecule drugs. May267 shows moderate HDAC1 inhibitory activity, which can be further optimized as a lead compound. However, it still has the problem of poor kinase selectivity to be solved.

Abstract 319: Small Molecule Gβγ Inhibition Attenuates Cardiac Fibroblast Inflammatory and Pro-Fibrotic Signaling

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Joshua G Travers ◽  
Fadia A Kamal ◽  
Michael S Burhans ◽  
Burns C Blaxall
Keyword(s):  
Myocardial Fibrosis ◽  
Inflammatory Cytokines ◽  
Small Molecule ◽  
Therapeutic Potential ◽  
Interstitial Fibrosis ◽  
Pressure Overload ◽  
Cardiac Fibroblast ◽  
Ventricular Compliance ◽  
Pro Inflammatory Cytokines

Heart failure (HF) is a devastating disease characterized by chamber remodeling, interstitial fibrosis and reduced ventricular compliance. Prolonged sympathetic overstimulation promotes excess signaling through G-protein Gβγ subunits and ultimately results in pathologic GRK2-mediated β-adrenergic receptor (β-AR) downregulation. We have recently demonstrated the therapeutic potential of the small molecule Gβγ-GRK2 inhibitor Gallein in limiting HF progression. Pathologic activation of the cardiac fibroblast (CF) induces the transition to a myofibroblast phenotype, which plays a fundamental role in myocardial fibrosis and remodeling. We hypothesized that Gβγ-GRK2 inhibition plays an important functional role in the CF to attenuate pathologic CF activation, inflammation and interstitial fibrosis. To explore the effect of Gβγ-GRK2 inhibition on inflammation and pro-fibrotic signaling, mice were subjected to 7 days of transverse aortic constriction, a pressure-overload model of HF. In addition to the attenuation in overall cardiac hypertrophy, animals treated with Gallein displayed reduced expression of pro-inflammatory cytokines, including macrophage inflammatory protein 1 alpha (MIP-1α) and MIP-1β, along with Interleukin-6, as assessed by qPCR. Gallein-treated animals also exhibited diminished pro-fibrotic signaling, as evidenced by a reduction in the expression of TGFβ, a major driver of myocardial fibrosis, and decreased expression of collagen. To recapitulate these findings in vitro, primary adult mouse ventricular fibroblasts were pathologically stimulated using Isoproterenol (ISO, β-AR agonist) or Angiotensin II and treated +/- Gallein for 24 hours. CFs treated with Gallein displayed an analogous reduction in the expression of these pro-inflammatory cytokines and collagen. In summary, these data suggest a potential therapeutic role for small molecule Gβγ-GRK2 inhibition in limiting pathologic myofibroblast activation, inflammation and interstitial fibrosis. We believe this fibroblast-targeted approach will lead to the refinement of existing targets and compounds, and possibly the generation of novel therapeutics for the treatment of HF.

scholarly journals Identification of potential TNF-α inhibitors: from in silico to in vitro studies

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Komal Zia ◽  
Sajda Ashraf ◽  
Almas Jabeen ◽  
Maria Saeed ◽  
Mohammad Nur-e-Alam ◽  
...  
Keyword(s):  
Small Molecule ◽  
Therapeutic Potential ◽  
Pharmacophore Model ◽  
Docking Studies ◽  
Immune Functions ◽  
Binding Interaction ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Potential Inhibitors

AbstractTumor Necrosis Factor Alpha (TNF-α) is a pleiotropic pro-inflammatory cytokine. It act as central biological regulator in critical immune functions, but its dysregulation has been linked with a number of diseases. Inhibition of TNF-α has considerable therapeutic potential for diseases such as cancer, diabetes, and especially autoimmune diseases. Despite the fact that many small molecule inhibitors have been identified against TNF-α, no orally active drug has been reported yet which demand an urgent need of a small molecule drug against TNF-α. This study focuses on the development of ligand-based selective pharmacophore model to perform virtual screening of plant origin natural product database for the identification of potential inhibitors against TNF-α. The resultant hits, identified as actives were evaluated by molecular docking studies to get insight into their potential binding interaction with the target protein. Based on pharmacophore matching, interacting residues, docking score, more affinity towards TNF-α with diverse scaffolds five compounds were selected for in vitro activity study. Experimental validation led to the identification of three chemically diverse potential compounds with the IC50 32.5 ± 4.5 µM, 6.5 ± 0.8 µM and 27.4 ± 1.7 µM, respectively.

scholarly journals Discovery of New Selective Butyrylcholinesterase (BChE) Inhibitors with Anti-Aβ Aggregation Activity: Structure-Based Virtual Screening, Hit Optimization and Biological Evaluation

Molecules ◽  
2019 ◽  
Vol 24 (14) ◽  
pp. 2568 ◽  
Author(s):  
Cheng-Shi Jiang ◽  
Yong-Xi Ge ◽  
Zhi-Qiang Cheng ◽  
Yin-Yin Wang ◽  
Hong-Rui Tao ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Cell Model ◽  
Neuroblastoma Cells ◽  
Biological Evaluation ◽  
Dynamics Simulation ◽  
Dependent Manner ◽  
Binding Modes ◽  
Catalytic Active Site ◽  
Aggregation Activity

In this study, a series of selective butyrylcholinesterase (BChE) inhibitors was designed and synthesized from the structural optimization of hit 1, a 4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzoic acid derivative identified by virtual screening our compound library. The in vitro enzyme assay results showed that compounds 9 ((4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenyl)(pyrrolidin-1-yl)methanone) and 23 (N-(2-bromophenyl)-4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzamide) displayed improved BChE inhibitory activity and good selectivity towards BChE versus AChE. Their binding modes were probed by molecular docking and further validated by molecular dynamics simulation. Kinetic analysis together with molecular modeling studies suggested that these derivatives could target both the catalytic active site (CAS) and peripheral anionic site (PAS) of BChE. In addition, the selected compounds 9 and 23 displayed anti-Aβ1–42 aggregation activity in a dose-dependent manner, and they did not show obvious cytotoxicity towards SH-SY5Y neuroblastoma cells. Also, both compounds showed significantly protective activity against Aβ1-42-induced toxicity in a SH-SY5Y cell model. The present results provided a new valuable chemical template for the development of selective BChE inhibitors.

scholarly journals Targeting Histone Deacetylases: A Novel Approach in Parkinson’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Sorabh Sharma ◽  
Rajeev Taliyan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcriptional Activation ◽  
Histone Deacetylases ◽  
Therapeutic Potential ◽  
Hdac Inhibitors ◽  
Clinical Manifestations ◽  
Future Research

The worldwide prevalence of movement disorders is increasing day by day. Parkinson’s disease (PD) is the most common movement disorder. In general, the clinical manifestations of PD result from dysfunction of the basal ganglia. Although the exact underlying mechanisms leading to neural cell death in this disease remains unknown, the genetic causes are often established. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the neurological disease conditions. The acetylation and deacetylation of histone proteins are carried out by opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. In the recent past, studies with HDAC inhibitors result in beneficial effects in bothin vivoandin vitromodels of PD. Various clinical trials have also been initiated to investigate the possible therapeutic potential of HDAC inhibitors in patients suffering from PD. The possible mechanisms assigned for these neuroprotective actions of HDAC inhibitors involve transcriptional activation of neuronal survival genes and maintenance of histone acetylation homeostasis, both of which have been shown to be dysregulated in PD. In this review, the authors have discussed the putative role of HDAC inhibitors in PD and associated abnormalities and suggest new directions for future research in PD.

A novel small-molecule screening strategy identifies mitoxantrone as a RhoGTPase inhibitor

2013 ◽  
Vol 450 (1) ◽  
pp. 55-62 ◽  
Author(s):  
Aurélien Bidaud-Meynard ◽  
Daniela Arma ◽  
Said Taouji ◽  
Michel Laguerre ◽  
Jean Dessolin ◽  
...  
Keyword(s):  
Small Molecule ◽  
High Throughput Screening ◽  
Large Scale ◽  
Topoisomerase Ii ◽  
Screening Strategy ◽  
Filamentous Actin ◽  
Library Screen ◽  
Rac1 Gtpase ◽  
Gtpase Activation

RhoGTPases are GDP/GTP molecular switches that control a wide variety of cellular processes, thereby contributing to many diseases, including cancer. As a consequence, there is great interest in the identification of small-molecule inhibitors of RhoGTPases. In the present paper, using the property of GTP-loaded RhoGTPases to bind to their effectors, we describe a miniaturized and robust assay to monitor Rac1 GTPase activation that is suitable for large-scale high-throughput screening. A pilot compound library screen revealed that the topoisomerase II poison MTX (mitoxantrone) is an inhibitor of Rac1, and also inhibits RhoA and Cdc42 in vitro. We show that MTX prevents GTP binding to RhoA/Rac1/Cdc42 in vitro. Furthermore, MTX strongly inhibits RhoGTPase-mediated F-actin (filamentous actin) reorganization and cell migration. Hence, we report a novel biochemical assay yielding the identification of RhoGTPase inhibitors and we present a proof-of-concept validation with the identification of MTX as a novel pan-RhoGTPase inhibitor.

Wogonin induces G1 phase arrest through inhibiting Cdk4 and cyclin D1 concomitant with an elevation in p21Cip1 in human cervical carcinoma HeLa cells

2009 ◽  
Vol 87 (6) ◽  
pp. 933-942 ◽  
Author(s):  
Li Yang ◽  
Hai-wei Zhang ◽  
Rong Hu ◽  
Yong Yang ◽  
Qi Qi ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Cervical Carcinoma ◽  
Hela Cells ◽  
Therapeutic Potential ◽  
P53 Gene ◽  
Mrna Levels ◽  
Human Cervical Carcinoma ◽  
Phase Arrest

Wogonin, a naturally occurring flavonoid, has been shown to have tumor therapeutic potential both in vitro and in vivo. To better understand its anticancer mechanism, we examined the effect of wogonin on human cervical carcinoma HeLa cells. In this study, we observed that G1 phase arrest was involved in wogonin-induced growth inhibition in HeLa cells. Over a 24 h exposure of HeLa cells to 90 µmol·L–1 wogonin, the promoters of G1–S transition, including cyclin D1/Cdk4 and pRb, decreased within 12 h and E2F-1 depleted in the nucleus at the same time. As the G1 phase arrest developed, p53 and the Cdk inhibitor p21Cip1 elevated both at protein and mRNA levels. Furthermore, the up-regulation of p21Cip1 induced by wogonin was dramatically inhibited by siRNA-mediated p53 gene silencing. Collectively, our data suggested that wogonin induced G1 phase arrest in HeLa cells by modulating several key G1 regulatory proteins, such as Cdk4 and cyclin D1, as well as up-regulation of a p53-midiated p21Cip1 expression. This mechanism of wogonin may play an important role in the killing of cancerous cells and offer a potential mechanism for its anticancer action in vivo.

First identification of small-molecule inhibitors of Pontin by combining virtual screening and enzymatic assay

2012 ◽  
Vol 443 (2) ◽  
pp. 549-559 ◽  
Author(s):  
Judith Elkaim ◽  
Michel Castroviejo ◽  
Driss Bennani ◽  
Said Taouji ◽  
Nathalie Allain ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Small Molecule ◽  
Tumour Cell ◽  
Small Molecule Inhibitors ◽  
Colorimetric Assay ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Atp Binding Site ◽  
Set Up

The human protein Pontin, which belongs to the AAA+ (ATPases associated with various cellular activities) family, is overexpressed in several cancers and its silencing in vitro leads to tumour cell growth arrest and apoptosis, making it a good target for cancer therapy. In particular, high levels of expression were found in hepatic tumours for which the therapeutic arsenal is rather limited. The three-dimensional structure of Pontin has been resolved previously, revealing a hexameric assembly with one ADP molecule co-crystallized in each subunit. Using Vina, DrugScore and Xscore, structure-based virtual screening of 2200 commercial molecules was conducted into the ATP-binding site formed by a dimer of Pontin in order to prioritize the best candidates. Complementary to the in silico screening, a versatile and sensitive colorimetric assay was set up to measure the disruption of the ATPase activity of Pontin. This assay allowed the determination of inhibition curves for more than 20 top-scoring compounds, resulting in the identification of four ligands presenting an inhibition constant in the micromolar concentration range. Three of them inhibited tumour cell proliferation. The association of virtual screening and experimental assay thus proved successful for the discovery of the first small-molecule inhibitors of Pontin.

scholarly journals Structure based virtual screening identifies novel competitive inhibitors for the sialoglycan binding protein Hsa

2020 ◽  
Author(s):  
Rupesh Agarwal ◽  
Barbara A. Bensing ◽  
Dehui Mi ◽  
Paige N. Vinson ◽  
Jerome Baudry ◽  
...  
Keyword(s):  
Virtual Screening ◽  
In Silico ◽  
Critical Role ◽  
Human Platelets ◽  
Screening Strategy ◽  
T Antigen ◽  
Bacterial Attachment ◽  
Bacterial Surface ◽  
Adhesin Protein

AbstractInfective endocarditis (IE) is a cardiovascular disease often caused by bacteria of the viridans group of streptococci, which includes Streptococcus gordonii and Streptococcus sanguinis. Previous research has found that a serine-rich repeat (SRR) proteins on the S. gordonii bacterial surface play a critical role in pathogenesis by facilitating bacterial attachment to sialyated glycans displayed on human platelets. Despite its important role in disease progression, there are currently no anti-adhesive drugs available on the market. Here, we performed structure-based virtual screening using an ensemble docking approach followed by consensus scoring to identify novel inhibitors against the sialoglycan binding domain of the SRR adhesin protein Hsa from the S. gordonii strain DL1. In silico cross screening against the glycan binding domains of closely related SRR proteins from five other S. gordonii or S. sanguinis strains was also performed to further reduce false positives. Using our in silico screening strategy we successfully predicted nine compounds which were able to displace the native ligand (sialyl-T antigen) in an in vitro assay and bind competitively to adhesin protein Hsa (∼20% hit rate).

scholarly journals Identification of Novel Chemical Entities for Adenosine Receptor Type 2A Using Molecular Modeling Approaches

Molecules ◽  
2020 ◽  
Vol 25 (5) ◽  
pp. 1245 ◽  
Author(s):  
Kelton L. B. dos Santos ◽  
Jorddy N. Cruz ◽  
Luciane B. Silva ◽  
Ryan S. Ramos ◽  
Moysés F. A. Neto ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Virtual Screening ◽  
Adenosine Receptor ◽  
Pharmacophore Model ◽  
Qsar Model ◽  
Positive Control ◽  
Receptor Type ◽  
Binding Modes

Adenosine Receptor Type 2A (A2AAR) plays a role in important processes, such as anti-inflammatory ones. In this way, the present work aimed to search for compounds by pharmacophore-based virtual screening. The pharmacokinetic/toxicological profiles of the compounds, as well as a robust QSAR, predicted the binding modes via molecular docking. Finally, we used molecular dynamics to investigate the stability of interactions from ligand-A2AAR. For the search for A2AAR agonists, the UK-432097 and a set of 20 compounds available in the BindingDB database were studied. These compounds were used to generate pharmacophore models. Molecular properties were used for construction of the QSAR model by multiple linear regression for the prediction of biological activity. The best pharmacophore model was used by searching for commercial compounds in databases and the resulting compounds from the pharmacophore-based virtual screening were applied to the QSAR. Two compounds had promising activity due to their satisfactory pharmacokinetic/toxicological profiles and predictions via QSAR (Diverset 10002403 pEC50 = 7.54407; ZINC04257548 pEC50 = 7.38310). Moreover, they had satisfactory docking and molecular dynamics results compared to those obtained for Regadenoson (Lexiscan®), used as the positive control. These compounds can be used in biological assays (in vitro and in vivo) in order to confirm the potential activity agonist to A2AAR.

scholarly journals Discovery of Two Brominated Oxindole Alkaloids as Staphylococcal DNA Gyrase and Pyruvate Kinase Inhibitors via Inverse Virtual Screening

2020 ◽  
Vol 8 (2) ◽  
pp. 293 ◽  
Author(s):  
Ahmed M. Sayed ◽  
Hani A. Alhadrami ◽  
Seham S. El-Hawary ◽  
Rabab Mohammed ◽  
Hossam M. Hassan ◽  
...  
Keyword(s):  
Natural Products ◽  
Virtual Screening ◽  
Pyruvate Kinase ◽  
Inhibitory Activity ◽  
In Silico ◽  
Kinase Inhibitors ◽  
Enzyme Inhibitor ◽  
Dna Gyrase ◽  
Binding Mode

In the present study, a small marine-derived natural products library was assessed for antibacterial potential. Among 36 isolated compounds, a number of bis-indole derivatives exhibited growth-inhibitory activity towards Gram-positive strains (Bacillus subtilis and multidrug-resistant Staphylococcus aureus). 5- and 6-trisindoline (5-Tris and 6-Tris) were the most active derivatives (minimum inhibitory concentration, MIC, 4–8 µM) that were subsequently selected for anti-biofilm activity evaluation. Only 5-Tris was able to inhibit the staphylococcal biofilm formation starting at a 5 µM concentration. In order to investigate their possible molecular targets, both natural products were subjected to in silico inverse virtual screening. Among 20 target proteins, DNA gyrase and pyruvate kinase were the most likely to be involved in the observed antibacterial and anti-biofilm activities of both selected natural products. The in vitro validation and in silico binding mode studies revealed that 5-Tris could act as a dual enzyme inhibitor (IC50 11.4 ± 0.03 and 6.6 ± 0.05 µM, respectively), while 6-Tris was a low micromolar gyrase-B inhibitor (IC50 2.1 ± 0.08 µM), indicating that the bromine position plays a crucial role in the determination of the antibacterial lead compound inhibitory activity.

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